Gangliosides are membrane-bound glycolipid molecules found in all vertebrate tissues, but particularly prominent in neural tissue. They are synthesized via two pathways designated "a" (predominant in adult brain), and "b" (predominant in fetal brain). Experimental evidence supports a role for gangliosides in the clinical behavior of several human tumors, including neuroblastoma. Our preliminary data demonstrate that fetal patterns of ganglioside biosynthesis predominate in neuroblastoma tumors from patients less than 1 year of age, those with low stage disease, whereas the adult patterns predominate in tumors from older children and those with disseminated disease. Our data also demonstartes improved outcome among NB patients with tumors containing a predomince (less than 60 percent) of "b" pathway gangliosides. Further, we have demonstrated that the downstream "b" pathway ganglioside, GT1b is absent from disseminated tumors, but not from lower stage tumors. In light of our work and published studies demonstrating that the "b" pathway gangliosides GD1b, GT1b, and GQ1b (immediately downstream from GD2) are absent in aggressive tumors, we hypothesize that the lack of terminal "b" pathway gangliosides may be related to the aggressive behavior of certain neuroblastomas, and is attributable to a defect in one of the "b" pathway biosynthetic enzymes. We will test this hypothesis by elucidating the association between patterns of "b" pathway ganglioside biosynthesis and the clinical behavior of neuroblastoma tumors. We will then delineate the enzymatic lesions associated with altered ganglioside biosynthesis in these tumors. These studies will pinpoint the ganglioside marker(s) associated with aggressive disease in neuroblastoma, and provide the basis for the development of a model system to test potential therapies aimed at modulating altered ganglioside biosynthesis as an approach to improving the clinical outcome of patients with aggressive neuroblastoma.